Despite potentially curative therapies, the majority of patients with treated metastatic sarcoma die as a result of subsequent disease relapse. The one-year disease-free survival rates and overall survival at 3 years following complete resection of recurrent metastatic disease in adult sarcoma patients or following combination therapy in pediatric sarcoma patients is less than 20%. Given the poor clinical outcome of these patients, the development of effective adjuvant therapy aimed at eliminating micrometastatic disease is desperately needed. The gangliosides GM2, GD2 and GD3 represent the three most prevalent cell surface antigens on sarcomas, and gangliosides have been shown to be effective targets for immune control of cancer, especially in the adjuvant setting. In adjuvant trials, the primary targets are individual circulating tumor cells or micrometastases which may persist for long periods after treatment of all known residual tumor. Antibodies induced by a trivalent vaccine against GM2, GD2 and GD3 are ideally suited for eradication of free tumor cells and micrometastases. If antibodies of sufficient titer can be induced against these antigens such that they eliminate these tumor cells from the blood and eradicate micrometastases, our approach to treating the sarcoma patient would be dramatically changed. MSKCC is the only center that has demonstrated the ability to consistently induce antibodies against these gangliosides in patients. Safety and immunogenicity of each individual component of the vaccine has already been demonstrated in patients. If the impact of vaccination on the clinical course of sarcoma is to be tested, a randomized, double-blind clinical trial is required. With the development and production of this trivalent ganglioside vaccine at MSKCC, we are now in a position to evaluate the impact of this vaccine in sarcoma patients on disease free and overall survival. The primary aim of this proposal is to determine whether the median disease-free survival or survival at 3 years after treatment with a trivalent ganglioside-KLH conjugate vaccine plus immunological adjuvant QS-DG (a synthetic version of QS-21) is greater compared to treatment with QS-DG alone in patients with metastatic sarcoma rendered disease free by single- or multi-modality therapy. 140 patients will be accrued over 2 years. All patients in this randomized, double blind trial will receive 8 vaccinations over 1 year and will be followed at MSKCC. Secondary aims are 1) to evaluate the toxicity of this regimen in this patient population, 2) to analyze the serological response in vaccinated patients to confirm vaccine stability over time, and 3) to correlate antibody response against the individual gangliosides with clinical course and antigens expressed in recurrences. PUBLIC HEALTH RELEVANCE: The double blind, randomized clinical trial proposed here will test whether a trivalent KLH conjugate vaccine that induces antibodies against 3 abundantly expressed sarcoma antigens can prevent outgrowth of circulating sarcoma cells and micrometastases. If antibodies of sufficient titer can be induced against these antigens such that they eliminate these tumor cells from the blood and eradicate micrometastases, our approach to treating the sarcoma patient would be dramatically changed. The establishment of new metastases would no longer be possible, so aggressive local therapies including surgery and radiation therapy might result in long-term control or potential cure of even metastatic sarcoma. [unreadable] [unreadable] [unreadable]